Jie Song#,Jiangnan Li#,Shuai Li,Gaihong Zhao,Tingting Li,Xin Chen,Boli Hu,Jia Liu,Xinyu Lai,Sitong Liu,Qiongqiong Zhou,Li Huang,Changjiang Weng

J Virol.2024 Dec 17:e0170124.doi: 10.1128/jvi.01701-24. Online ahead of print.

Abstract

During viral infections, autophagy functions as a cell-intrinsic defense mechanism by facilitating the delivery of virions or viral components to the endosomal/lysosomal pathway for degradation. In this study, we report that internalized African swine fever virus (ASFV) virions enter autolysosomes during the early phase of viral infection. Autophagy selectively targets the major capsid protein p72 within the ASFV virion. The ASFV p72 protein undergoes modification through ubiquitination at the C-terminus, a process mediated by the E3 ubiquitin ligase Stub1. Subsequently, ubiquitinated p72 is recognized by the autophagy receptor SQSTM1/p62 through its ubiquitin-binding domain. Stub1 facilitates the ubiquitination and degradation of p72 in an HSPA8-dependent manner  via  selective autophagy. Autophagy plays a critical role in disassembling ASFV virions and further promotes the release of ASFV genomic DNA. These findings support the notion that autophagy is involved in and contributes to the capsid disassembly of ASFV, providing valuable insights into this essential viral process.IMPORTANCEAfrican swine fever (ASF), a highly contagious disease caused by the ASF virus (ASFV), affects domestic pigs and wild boars, with a mortality rate of up to 100%. The ASF epidemic poses a persistent threat to the global pig industry. Currently, no effective vaccines or antiviral drugs are available for prevention and control. In this study, we discovered that autophagy promotes the degradation of p72 and the disassembly of the capsid during the early phase of ASFV infection. Mechanically, Stub1 facilitates the polyubiquitination of ASFV p72 through the chaperone HSPA8. The polyubiquitinated p72 then interacts with the autophagy receptor SQSTM1/p62, leading to its degradation  via  the selective autophagy pathway. These findings reveal the mechanism of p72 degradation through autophagy and provide new insights into the capsid disassembly process of ASFV.

Keywords: African swine fever virus; HSPA8; Stub1; capsid disassembly; p72; selective autophagy.